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Abstract: Heap leaching is a technology for which there is great interest in developing mathematical models that allow one to simulate, design and optimise the underlying process. Recently, the authors have presented analytical models for heap leaching that describe time scales for the particle and the heap in a rather simple model but with enough accuracy to be applied in the planning, optimisation, control and design of heap leaching. The simplicity of these models allows us to overcome the mathematical complexities of partial differential equation-based models and the error of empirical models. In this work, we present these analytical models, and then show how uncertainty in the input variables and parameters affects the response of the process by comparing the response curve with fixed parameters to the ones with uncertainty. Here we present simulation experiments of heap leaching processes under uncertainties based upon analytical models and using Monte Carlo techniques. We conclude that, in some cases, there exists an important influence of the input variables’ uncertainty on the response of the heap leaching process. [Copyright &y& Elsevier]

Abstract: In this paper we present analytical models suitable for scaling up the heap leaching process of solid reactants from porous pellets. The models are based on first order ordinary differential equations together with some constitutive relations derived from models based on ordinary and partial differential equations and other relations based on insight. The models are suitable for applications in which the scale-up is neccesary. This approach allows to obtain accurate solutions for actual industry heap leaching operations. Novelty of this approach is the simple form of the models and its accuracy as compared with more complex models. Due to the models simplicity, they can be used for analysis, design, control and optimization of heap leaching processes without mathematical complexities. The models include the effect of heap height, particle sizes, flow rates, and several operation-design variables. Finally, some numerical experiments which confirm our theory are presented. [ABSTRACT FROM AUTHOR]

Abstract: Chemokines belong to a family of structurally related chemoattractant proteins that bind to specific seven‐transmembrane receptors linked to G proteins. They are implicated in a variety of biologic responses ranging from cell polarization, movement, immune and inflammatory responses, as well as prevention of HIV‐1 infection and cancer metastasis. Recent evidence indicates that chemokine receptors can adopt several conformations at the cell membrane. Chemokine receptor homo‐ and heterodimers preexist on the cell surface, even in the absence of ligands. Chemokine binding stabilizes specific receptor conformations and activates distinct signaling cascades. Analysis of the conformations adopted by the receptors at the membrane and their dynamics is crucial for a complete understanding of the function of these inflammatory mediators. We focus here on conventional biochemical and genetic methods, as well as on new imaging techniques such as those based on resonance energy transfer, discussing their advantages, disadvantages, and possible complementarity in the analysis of chemokine receptor dimerization. [Copyright &y& Elsevier]

Abstract: In this paper we present an alternative method based on analytical and numerical solutions for solving the differential equations which describe heap leaching of one or more solid reactants from porous pellets. We propose to use analytical solutions for the differential equations which describe rate dissolutions along the pores and the surface of the particles under suitable regularity conditions. Moreover, we propose to use continuous and discontinuous solutions for the continuity partial differential equations describing balances. We comment on the efficient numerical solving of the remaining partial differential equations within the proposed numerical scheme. All of this, allows to obtain a numerical algorithm which is fast and accurate for the heap leaching problem. Also, we include particle size distributions on the proposed numerical methodology. This method applies to the case where the rate-controlling reagent is a component of the lixiviation solution only and not of the gas phase. The model includes the effects of particle scales, kinetic factors, heap scales and several operation variables. Finally, numerical experiments are presented. [Copyright &y& Elsevier]

Abstract: Our current knowledge of molecular and cellular responses in vivo is based mainly on event reconstruction from time-freeze observations. Conventional biochemical and genetic methods consider the cell as an individual entity and ligand/receptor pairs as isolated systems. In addition, the data refer to the average behavior of a pool of cells and/or receptors removed from their real-life context. The use of new technologies, particularly real-time imaging approaches, is showing us that biological responses are highly dynamic and extremely dependent on the context in which they take place, and therefore much more diverse than initially envisaged. This review focuses on the mechanistic insights that new imaging techniques, such as those based on resonance energy transfer and two-photon microscopy, contribute to our understanding of how receptors work within a single cell, and how cells work within a tissue. Cell movement is a complex and regulated process; it has a key role in embryogenesis, organogenesis, wound-healing and tumor invasion. Nonetheless, it is in immune system homeostasis and response that cell movement becomes essential. For this reason, immunology is being radically transformed and enriched by these new approaches. We will discuss the use of these techniques for studying chemokine/chemokine receptors and their role in the immune system function, and comment on the potential contribution to the design of therapeutic strategies. [Copyright &y& Elsevier]

Abstract: Antofagasta, Chile, has one of the most important deposits of saltpetre in the world, which is called caliche. These deposits are mainly composed of nitrate, halite, sodium anorthite, and quartz. Minor species include anhydrite, glauberite, loeweite, calcite, polyhalite, probertite, and gypsum. Recently, several operations began to use heap leaching for the extraction of saltpetre. Modelling the heap leaching of caliche is not straightforward because of the many minerals and their different dissolution rates. Moreover, caliche may have a large fraction of soluble minerals, approximately 40%, which causes the heap to slump. In this work, we present two models. The first, which is a phenomenological model, is an extension of the model published by . The system is modelled as a column comprised of N small columns, and in each of these small columns, the height of the solids varies with time when the soluble minerals are dissolved. The liquid in each small column has the same composition (well-stirred reactor). The second model, which is an analytical model, is an extension of that published by for low-grade minerals, such as copper and gold, which considers that the leaching phenomenon occurs on different scales of size and time. However, in this work, the time scale at the particle level is based on the Bruner and Tolloczko dissolution model. The objective of this work is to test the suitability of the analytical model as a tool for use in optimisation, for which the model needs to be solved many times. The phenomenological model was used to generate simulated experimental data. The results show that the analytical model may be a useful tool in optimisation. [Copyright &y& Elsevier]

Chemokine receptor CCR7 directs mature dendritic cells (mDCs) to secondary lymph nodes where these cells regulate the activation of T cells. CCR7 also promotes survival in mDCs, which is believed to take place largely through Akt-dependent signaling mechanisms. We have analyzed the involvement of the AMP-dependent kinase (AMPK) in the control of CCR7-dependent survival. A pro-apoptotic role for AMPK is suggested by the finding that pharmacological activators induce apoptosis, whereas knocking down of AMPK with siRNA extends mDC survival. Pharmacological activation of AMPK also induces apoptosis of mDCs in the lymph nodes. Stimulation of CCR7 leads to inhibition of AMPK, through phosphorylation of Ser-485, which was mediated by Gi/Gβγ, but not by Akt or S6K, two kinases that control the phosphorylation of AMPK on Ser-485 in other settings. Using selective pharmacological inhibitors, we show that CCR7-induced phosphorylation of AMPK on Ser-485 is mediated by MEK and ERK. Coimmunoprecipitation analysis and proximity ligation assays indicate that AMPK associates with ERK, but not with MEK. These results suggest that in addition to Akt-dependent signaling mechanisms, CCR7 can also promote survival of mDCs through a novel MEK1/2-ERK1/2-AMPK signaling axis. The data also suggest that AMPK may be a potential target to modulate mDC lifespan and the immune response. [ABSTRACT FROM AUTHOR]

Abstract: Since the first reports on chemokine function, much information has been generated on the implications of these molecules in numerous physiological and pathological processes, as well as on the signaling events activated through their binding to receptors. Despite these extensive studies, no chemokine-related drugs have yet been approved for use in patients with inflammatory or autoimmune diseases. This discrepancy between efforts and results has forced a re-evaluation of the chemokine field. We have explored chemokine receptor conformations at the cell surface and found that, as is the case for other G protein-coupled receptors, chemokine receptors are not isolated entities that are activated following ligand binding; rather, they are found as dimers and/or higher order oligomers at the cell surface, even in the absence of ligands. These complexes form organized arrays that can be modified by receptor expression and ligand levels, indicating that they are dynamic structures. The way in which these receptor complexes are stabilized modulates ligand binding, as well as their pharmacological properties and the signaling events activated. These conformations thus represent a mechanism that increases the broad variety of chemokine functions. Understanding these receptor interactions and their dynamics at the cell surface is thus critical for influencing chemokine function and could open up new possibilities for drug design. [Copyright &y& Elsevier]

In this study, we have investigated the role of CD69, an early inducible leukocyte activation receptor, in murine dendritic cell (DC) differentiation, maturation, and migration. Skin DCs and DC subsets present in mouse lymphoid organs express CD69 in response to maturation stimuli. Using a contact sensitization model, we show that skin DCs migrated more efficiently to draining lymph nodes (LNs) in the absence of CD69. This was confirmed by subcutaneous transfer of CD69-/- DCs, which presented an increased migration to peripheral LNs. Two-photon microscopy analysis showed that once DCs reached the LNs, CD69 deficiency did not alter DC interstitial motility in the LNs. Chemotaxis to sphingosine-1-phosphate (S1P) was enhanced in CD69-/- DCs compared with wild-type DCs. Accordingly, we detected a higher expression of S1P receptor type-1 (S1P1) by CD69-/- DCs, whereas S1P3 expression levels were similar in wild-type and CD69-/- DCs. Moreover, in vivo treatment with S1P analogs SEW2871 and FTY720 during skin sensitization reduced skin DC migration to peripheral LNs. These results suggest that CD69 regulates S1P-induced skin DC migration by modulating S1P1 function. Together, our findings increase our knowledge on DC trafficking patterns in the skin, enabling the development of new directed therapies using DCs for antigen (Ag) delivery. [ABSTRACT FROM AUTHOR]

The chemokines, a family of structurally related chemoattractant proteins that bind to specific seven-transmembrane receptors linked to G proteins, trigger a broad array of biological responses ranging from cell polarization, movement, immune and inflammatory responses to prevention of HIV-1 infection. Chemokine-mediated cell activation was thought to be due to the binding of a monomeric chemokine to its monomeric receptor. Chemokine biology is nonetheless more complex than was initially predicted, as several studies suggest that chemokines can dimerize and that their receptors are found as dimers and/or higher order oligomers at the cell surface. There is also evidence that they cluster in arrays, rather like bundles of cigars. Here we evaluate how these arrays might be organized, the influence of ligand levels and receptor expression on them, and their influence on chemokine function. [Copyright &y& Elsevier]

Coordinated action between cytokines and chemokines is required for effective endocrine and immune responses. Proteins of both families promote receptor oligomerization, activation of the Janus kinase (JAK)/ STAT pathway, and transcription of many genes, including the suppressor of cytokine signaling (SOCS) family. In this study, we show that chemokine-mediated SOCS1 and SOCS3 up-regulation modulates the signaling and function associated to a cytokine receptor, both in vitro and in vivo. The effect is mediated by SOCS binding to JAK2 and to the cytokine receptor, which blocks subsequent signaling events. The data reinforce the premise of cytokine-chemokine cross-talk, which helps contribute to modulating individual responses and in defining the functional plasticity of the immune system. [ABSTRACT FROM AUTHOR]